Inflammatory bowel disease (IBD) encompasses Crohn's disease and Ulcerative colitis, diseases the cause of which is currently unknown. In recent years, tremendous progress has been made towards understanding the pathogenesis of IBD. The evidence strongly points to a role for both a microbial and an immune component. Several species of pathogenic bacteria residing within the gut lumen have been implicated, and these include invasive Escherichia coli, Helicobacter, Clostridium and Enterococcus species. Furthermore, increased levels of the inflammatory cytokines interleukin (IL)-17 and IL-23 have been reported within the intestinal mucosa. These two cytokines are critical for the function and maintenance of T helper type 17 (TH17) cells, a recently identified subset of helper T cells that play important roles in host defense and organ specific autoimmune inflammation. Genome wide array analyses have identified prominent IBD susceptibility genes involved in the IL-23-TH17 immune response pathway, immune suppression, and innate immunity to microbial pathogens. Collectively, these studies point to an imbalance in the symbiotic relationship between host and microbe, such that loss in tolerance to the intestinal microbiota and increased TH17 related inflammation are now considered to be responsible for the pathogenesis of IBD. The exact mechanisms for why and how this occurs in patients with IBD is unclear. Our recent identification of one physiological trigger that drives THI 7 responses within the intestinal lamina propria provides a clue. We found that innate immune recognition of apoptotic intestinal epithelial cells dying during an infection induces differentiation of naive CD4 T cells into effector TH17 cells. Here we aim to test our hypothesis that an inability to protect the intestinal epithelium during infections with damaging and invasive enteric pathogens serves as an instigator of IBD. We will characterize the antigen specificities of infection-induced THI 7 response to self and non-self antigens, and define the regulatory mechanisms that control self-specific populations. We will ask whether an absence or a dysfunction of these regulatory populations within a genetic susceptibility background for IBD, leads to failure in protecting and repairing the epithelium damaged from infection, progressive loss of barrier functions against luminal bacteria, and an inability to suppress the aggravated inflammatory response.